Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction.

Heatstroke (HS) can cause acute lung injury (ALI). Heat stress induces inflammation and apoptosis via reactive oxygen species (ROS) and endogenous reactive aldehydes. Endothelial dysfunction also plays a crucial role in HS-induced ALI. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies aldehydes such as 4-hydroxy-2-nonenal (4-HNE) protein adducts. A single point mutation in ALDH2 at E487K (ALDH2*2) intrinsically lowers the activity of ALDH2. Alda-1, an ALDH2 activator, attenuates the formation of 4-HNE protein adducts and ROS in several disease models. We hypothesized that ALDH2 can protect against heat stress-induced vascular inflammation and the accumulation of ROS and toxic aldehydes. Homozygous ALDH2*2 knock-in (KI) mice on a C57BL/6J background and C57BL/6J mice were used for the animal experiments. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro experiment. The mice were directly subjected to whole-body heating (WBH, 42°C) for 1 h at 80% relative humidity. Alda-1 (16 mg/kg) was administered intraperitoneally prior to WBH. The severity of ALI was assessed by analyzing the protein levels and cell counts in the bronchoalveolar lavage fluid, the wet/dry ratio and histology. ALDH2*2 KI mice were susceptible to HS-induced ALI in vivo. Silencing ALDH2 induced 4-HNE and ROS accumulation in HUVECs subjected to heat stress. Alda-1 attenuated the heat stress-induced activation of inflammatory pathways, senescence and apoptosis in HUVECs. The lung homogenates of mice pretreated with Alda-1 exhibited significantly elevated ALDH2 activity and decreased ROS accumulation after WBH. Alda-1 significantly decreased the WBH-induced accumulation of 4-HNE and p65 and p38 activation. Here, we demonstrated the crucial roles of ALDH2 in protecting against heat stress-induced ROS production and vascular inflammation and preserving the viability of ECs. The activation of ALDH2 by Alda-1 attenuates WBH-induced ALI in vivo.

Evaluation of and the prognostic factors for cats with big kidney-little kidney syndrome.

BACKGROUND: The term big kidney-little kidney syndrome in cats has been used for many years, but the definitions are not consistent and relevant research is limited. OBJECTIVE: To determine the factors that differ between normal and BKLK cats, as well as to develop models for predicting the 30-day survival of cats with ureteral obstruction (UO). ANIMALS: Sixteen healthy cats and 64 cats with BKLK. METHODS: Retrospective study. To define BKLK by reference to data from clinically healthy cats. The demographic and clinicopathological data among groups were statistically analyzed. RESULTS: Big kidney-little kidney syndrome cats had higher blood urea nitrogen (BUN) (median [interquartile range] 69 [28-162] vs 21 [19-24] mg/dL, P < .001), creatinine (5.6 [1.9-13.3] vs 1.3 [1.05-1.40] mg/dL, P < .001), and white blood cells (10 800 [7700-17 500] vs 6500 [4875-9350] /µL, P < .001) and lower hematocrit (32.8 [27.1-38.4] vs 39.1 [38.1-40.4]%, P < .001), urine specific gravity (1.011 [1.009-1.016] vs 1.049 [1.044-1.057], P < .001) and pH (5.88 [5.49-6.44] vs 6.68 [6.00-7.18], P = .001) compared to the control cats. A lower body temperature (BT; 38.1 [37.9-38.2] vs 38.7 [38.3-39.2]°C, P = .009), higher BUN (189 [150-252] vs 91 [36-170] mg/dL, P = .04), and creatinine (15.4 [13.3-17.4] vs 9.0 [3.1-14.2] mg/dL, P = .03) were found among the UO cats that were not 30-day survivors. A combination of BUN, phosphorus, and BT can predict 30-day survival among UO cats with an area under receiver operating characteristic curve of 0.863. (P = .01). CONCLUSION: An increase in the length difference between kidneys can indicate UO, but cannot predict outcome for BKLK cats.

Recreational ketamine-related deaths notified to the National Programme on Substance Abuse Deaths, England, 1997-2019.

BACKGROUND: Ketamine is a phencyclidine derivative with dissociative anaesthetic properties. Increasing numbers of individuals in England take ketamine recreationally. Information on deaths arising from such use in England is presented. METHODS: Cases were extracted on 31 January 2020 from the National Programme on Substance Abuse Deaths database, based on text searches of the cause of death, coroner's verdict and positive toxicology results for the terms 'ketamine' or 'norketamine'. FINDINGS: During 1997-2005, there were <5 deaths p.a. in which ketamine was implicated. Numbers increased until 2009 (21), plateauing until 2016; thereafter, deaths have risen to about 30 p.a. Decedents' characteristics (N = 283): male 84.1%, mean age 31.2 (SD 10.0) years, employed 56.5%, drug use history 79.6% and living with others 60.3%. Ketamine was detected with other substances in most cases. Main (74.6%) underlying cause of death was accidental poisoning. Ketamine may have impaired judgement in other cases. CONCLUSIONS: Although controlled, recreational ketamine use and related fatalities continue to increase. Consumers need to be more aware of the potentially fatal risks they face.

Evaluation of Endotracheal Tube Cuff Pressure and the Use of Three Cuff Inflation Syringe Devices in Dogs.

Over-inflation of an endotracheal tube (ETT) cuff may lead to tracheal mucosal irritation, tracheal wall ischemia or necrosis, whereas under-inflation increases the risk of pulmonary aspiration as well as leaking anesthetic gas and polluting the environment. The objectives of this two-phase study were to (1) identify the incidence of improper ETT cuff inflation (both over- and under-inflation) using the minimum occlusive volume (MOV) technique coupled with a regular injectable syringe in the anesthetized dogs, and (2) evaluate the performance of two commercially available inflation syringe devices (Tru-Cuff and AG Cuffill®) with the regular injectable syringe in inflating the ETT cuff to a recommended safe cuff pressure range (20-30 cmH2O). Dogs undergoing general anesthesia at Purdue Veterinary Medicine Teaching Hospital were included. The ETT cuff pressure was assessed with an aneroid manometer after the syringe inflation. The results of the first objective showed that a total of 80 dogs enrolled and that 50 of these 80 dogs required ETT cuff inflation. Among the 50 dogs, only 14% had proper ETT cuff inflation; 76% of the ETT cuffs were over-inflated and 10% were under-inflated. Ninety dogs were enrolled for the second objective study and they were randomly and equally assigned to the three syringe device treatment groups. The results showed that 80% of the ETT cuffs were over-inflated in the regular injectable syringe treatment group, whereas only 6.7% and 3.3% ETT cuffs were over-inflated in the Tru-Cuff and AG Cuffill® syringe treatment groups, respectively. The AG Cuffill® syringe treatment group had a significantly (p < 0.05) higher percentage of properly inflated ETT cuffs (86.7%) compared to the other two groups (regular injectable syringe [3.3%]; Tru-Cuff syringe [50%]. We concluded that there was a high incidence of improper ETT cuff inflation when using MOV technique coupled with a regular injectable syringe. The use of an AG Cuffill® syringe significantly reduced improper ETT cuff inflation.